The human gamma-herpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), establish persistent infections that are associated with the development of a variety of malignancies. Whereas the lytic phase of the infection is controlled by the immune system, the viruses evade immunity by establishing life-long latency, even in an immunocompetent host. Pathological consequences of infection are primarily associated with viral latency, and no prophylactic or therapeutic vaccines are available. B cells are the major reservoir of latent virus, and one important clinical problem associated with EBV infection is the development of B cell lymphoproliferative disease and/or B cell lymphomas following post-transplant immunosuppression. Promising results with the clinical use of Rituximab (anti-B cell antibody therapy) to target EBV-transformed B cells in post-transplant malignancies suggest the possibility that anti-B cell therapy could be used prophylactically to substantially lower latent load or even to purge latency from the host prior to transplantation. In order to test this and other therapeutic approaches, it is essential to understand mechanisms involved in maintenance of long-term latency, which can best be elucidated in an experimental animal model. Gamma HV68 (also referred to as MHV-68) is a naturally occurring gamma-herpesvirus of rodents that infects the laboratory mouse, providing an easily manipulated small animal natural infection model for performing experiments not possible in man. The current proposal exploits the mouse model to address mechanisms underlying the maintenance of latency. Importantly, we will test the hypothesis that latent virus can be purged from an infected host. In Aim 1, we will determine whether viral reactivation and re-infection contribute to the maintenance of long-term latency in B cells, macrophages and dendritic cells. In Aim 2 we will determine whether treatment with B cell depleting antibodies to mimic Rituximab therapy, with or without anti-viral drugs, can reduce or eliminate long-term latency. PUBLIC HEALTH RELEVANCE: The gamma-herpesviruses are oncogenic viruses that are widely disseminated in the human population and associated with the development of malignancies. Analysis of the well-developed mouse model of gamma- herpesvirus infection provides an important tool to dissect fundamental events in the reactivation of viral latency, and serves as an in vivo model for testing proof of concept therapeutic strategies. The data generated will advance the field by enhancing our understanding of gamma-herpesvirus latency to facilitate the development of therapeutic strategies for the human gamma-herpesviruses.